Malaria is a global infectious disease that causes profound morbidity and mortality. RTS,S - currently the most advanced malaria vaccine ? is based upon the Plasmodium circumsporozoite protein (CSP) in conjunction with immunostimulatory epitopes of the Hepatitis B surface antigen and AS01 adjuvant. To date, the CSP-based vaccine offers moderate protection with a 30-50% reduction in infection rate in selected groups of individuals, in clinical trials. Strategies to identify targets that synergize with CSP, or that work independently of CSP are needed for a highly effective vaccine. Plasmodium sporozoites are transmitted by Anopheline mosquitoes. Sporozoites are deposited into the skin of a vertebrate host following a mosquito bite, and then travel within blood vessels to the liver, where they invade hepatocytes and establish infection. Our preliminary data show that antiserum against mosquito salivary gland extracts influences the ability of mosquito-borne sporozoites to optimally infect the murine host. Using an A. gambiae salivary gland cDNA yeast surface display library, we identified a protein in saliva, AgTRIO, recognized by antiserum against A. gambiae salivary gland extracts. Administration of AgTRIO-antiserum to mice decreased the ability of mosquito-borne Plasmodium berghei or Plasmodium falciparum to cause hepatic infection in the animals. These data suggest that AgTRIO-antiserum influences sporozoites during the initial stage of Plasmodium infection -- when sporozoites are deposited into the skin following mosquito bite. This proposal will examine how AgTRIO-antiserum, or AgTRIO protein, influence sporozoites in the skin, as Plasmodium moves from the extracellular tissue to a blood vessel. These studies will elucidate how a mosquito salivary protein, and antiserum directed against this protein, alters Plasmodium activity in the skin, which may facilitate to develop a synergic vaccine strategy with current available vaccine to control malaria.